Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular weaponry deployed on both sides. Using a recursive computational approach, Dr. Aravind and his team was uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, Dr. Aravind and his team was termed them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid-binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.This was the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems. In a separate project to uncover regulatory mechanisms in Hedgehog (Hh) signaling, Dr. Aravind working in collaboration with Dr. Rajat Rohatgi's group at the Stanford university conducted genome-wide screens to identify positive and negative pathway components and validated top hits using multiple signaling and differentiation assays in two different cell types. Most positive regulators identified in our screens, including Rab34, Pdcl, and Tubd1, were involved in ciliary functions, confirming the central role for primary cilia in Hh signaling. Negative regulators identified included Megf8, Mgrn1, and an unannotated gene encoding a tetraspan protein they named Atthog. The function of these negative regulators converged on Smoothened (SMO), an oncoprotein that transduces the Hh signal across the membrane. In the absence of Atthog, SMO was stabilized at the cell surface and concentrated in the ciliary membrane, boosting cell sensitivity to the ligand Sonic Hedgehog (SHH) and consequently altering SHH-guided neural cell-fate decisions. Thus, they uncovered genes that modify the interpretation of morphogen signals by regulating protein-trafficking events in target cells. Residues responsible for allostery, cooperativity, and other subtle but functionally important interactions remain difficult to detect. To aid such detection, Dr Aravind working with Dr. Altschul and Dr. Neuwald's groups employed statistical inference based on the assumption that residues distinguishing a protein subgroup from evolutionarily divergent subgroups often constitute an interacting functional network. They identified such networks with the aid of two measures of statistical significance. One measure aids identification of divergent subgroups based on distinguishing residue patterns. For each subgroup, a second measure identifies structural interactions involving pattern residues. Such interactions are derived either from atomic coordinates or from Direct Coupling Analysis scores, used as surrogates for structural distances. Applying this approach to N-acetyltransferases, P-loop GTPases, RNA helicases, synaptojanin-superfamily phosphatases and nucleases, and thymine/uracil DNA glycosylases yielded results congruent with biochemical understanding of these proteins, and also revealed striking sequence-structural features overlooked by other methods. These and similar analyses can aid the design of drugs targeting allosteric sites. SH3-fold--barrel domains of the chromo-like superfamily recognize epigenetic marks in eukaryotic proteins. Their provenance has been placed either in archaea, based on apparent structural similarity to chromatin-compacting Sul7d and Cren7 proteins, or in bacteria based on the presence of sequence homologs. Using sequence and structural evidence Dr. Aravind and his team established that the archaeal Cren7/Sul7 proteins emerged from a zinc ribbon (ZnR) ancestor. Further, we show that the ancestral eukaryotic chromo-like domains evolved from bacterial versions, likely acquired from early endosymbioses, which already possessed an aromatic cage for recognition of modified amino-groups. These bacterial versions are part of a radiation of secreted SH3-fold domains, which spawned both chromo-like domains and classical SH3 domains in the context of peptide-recognition in the peptidoglycan or the extracellular matrix. This establishes that Cren7/Sul7 converged to a SH3-like state from a ZnR precursor via the loss of metal-chelation and acquisition of stronger hydrophobic interactions; it is unlikely to have participated in the evolution of the chromo-like domains. Dr. Aravind and his team showed that archaea possess several Cren7/Sul7-related proteins with intact Zn-chelating ligands, which Dr. Aravind and his team predict to play previously unstudied roles in chromosome segregation during cell-division comparable to the PRC barrel and CdvA domain proteins. Dr. Aravind's work was at the forefront of expanding the understanding of human and plant diseases. His work received over 4,800 citations in the scientific literature in the year 2016. Additionally, he was asked to serve as a peer reviewer for several manuscripts submitted to the journals Biology Direct, Cell, Nature, Science, Nucleic Acids Research, Current Opinions in Structural Biology, Current Topics in Microbiology and Immunology, Frontiers in Genetics, and PNAS. As an invited speaker at two conferences, he also presented several aspects of his research